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PURPOSE To compare the efficacy and toxicity profiles of a combination of fluorouracil (5-FU) with recombinant human interferon alfa-2a (Roferon-A; Hoffman La-Roche AG, Basel, Switzerland) versus the combination of 5-FU with leucovorin (LV) in the treatment of advanced colorectal cancer. PATIENTS AND METHODS A total of 496 previously untreated colorectal cancer patients were randomized to receive either Roferon-A (9 MIU) subcutaneously three times per week, with 5-FU (750 mg/m2/d) by continuous intravenous (i.v.) infusion (CIV) on days 1 to 5, then, after a 9-day hiatus, as a weekly i.v. bolus at the same dose (IFN/5-FU); or LV (200 mg/m2/d) by i.v. infusion plus 5-FU (370 mg/m2/d) by i.v. bolus on days 1 to 5, repeated every 4 weeks (LV/5-FU). RESULTS There were no significant differences between IFN/5-FU and LV/5-FU in the overall response rate (21% v 18%), duration of response (7.3 v 6.2 months), or survival time (median, 11.0 v 11.3 months). Toxicity profiles differed; constitutional symptoms and myelosuppression were more frequent and more severe with IFN/5-FU, and gastrointestinal symptoms with LV/5-FU. More patients interrupted treatment for adverse events (AEs) with IFN/5-FU than with LV/5-FU. Five treatment-related deaths occurred with each regimen. CONCLUSION The combination IFN/5-FU produced response rates, response durations, and survival times similar to those with LV/5-FU. Biochemical modulation of 5-FU by either IFN or LV appears to result in equivalent efficacy; however, fewer patients were able to tolerate the specified IFN/5-FU combination used in this study.

The paper presents and compares three methods making use of the singular value decomposition (SVD) of a matrix to extract the foetal electrocardiogram (FECG) from cutaneously recorded electrode signals. The first method constructs a set of orthogonal foetal signals (the so-called principal foetal signals) from the recordings, but needs electrode positions far from the foetal heart, in addition to the abdominal electrodes that pick up a mixture of maternal and foetal electrocardiogram. An online adaptive algorithm has been developed such that a real-time implementation becomes feasible. The second method is a new online approach to a technique presented by van Oosterom. Although this method has some important drawbacks and is suboptimal as far as foetal signal-to-noise ratio is concerned, it is still very useful when only a foetal trigger is required, as the signal obtained is not a complete FECG. Finally, a third method is proposed, based on the generalised SVD and interpreted with the new concept of oriented signal-to-signal ratio. An online version is also presented for this method and some results are shown.

The Velo-Cardio-Facial Syndrome (VCFS), caused by a submicroscopic deletion in the long arm of chromosome 22, has a broad clinical spectrum of ENT manifestations including for instance velopharyngeal dysfunction, hearing problems and laryngotracheal anomalies. In the current report we present guidelines for diagnosis, treatment and follow-up of the ENT manifestations in patients with a deletion 22q11, based on our experience and the literature.

Recently, we developed a disposable acid exposure sensor whose in vitro response to acid below pH 4 is linearly determined by the duration of exposure and the degree of acidity. The aim of the present study was to compare the SR to simultaneous esophageal pH and duodenogastroesophageal reflux (DGER) monitoring (Bilitec) in patients investigated for presumed gastroesophageal reflux disease (GERD). Twenty-six patients (16 men, mean age 46 +/- 2 years) with symptoms suggestive of GERD underwent 24-hr ambulatory pH monitoring and SR monitoring at 5 cm proximal to the LES. DGER monitoring was performed in 21 patients. Exposure of the esophagus to acid and to DGER were analyzed. These data were compared to SR. A significant correlation was found between the exposure of the distal esophagus to acid and SR (R = 0.85; P0.0001). Similarly, the area below a cutoff pH 4 was significantly correlated to SR (r = 0.81; P0.0001). SR was not correlated to DGER (r = 0.16; NS). At a cutoff of 50, the sensitivity and specificity of SR to predict esophageal acid exposure5% of time were 91% and 93%, respectively conclusion, the response of the acid exposure sensor is strongly correlated with the results of simultaneous esophageal pH monitoring. The sensor seems able to reliably predict pathological esophageal acid exposure. These findings warrant larger studies of the clinical potential of the acid exposure sensor in the diagnosis and quantification of GERD.

An adaptive system for the processing of electrogastric (EGG) signals that enhances the signals is proposed. The main disturbance, respiratory artifact, can be efficiently canceled and time variations of the gastric signal frequency can be monitored online. Results for four different positional EGG signals are presented and discussed. The algorithms used by the system are simple and easy to implement, and the system can be installed on a personal computer. >

The velo-cardio-facial syndrome (VCFS) is a leading cause of velopharyngeal dysfunction and cleft palate and caused by a submicroscopic deletion in the long arm of chromosome 22 (band 22q11). During the last 5 years, 130 patients with a 22q11 deletion were diagnosed in Leuven. Most patients presented a wide variety of the classical features of the velo-cardio-facial syndrome. Velopharyngeal dysfunction was almost always present whereas an isolated cleft lip/palate was observed in a minority of patients. The velopharyngeal function can be evaluated by the classic combination of indirect and direct techniques. Because of the frequent occurrence of the velo-cardio-facial syndrome, estimated at around 1/4000 live births, and given the extremely broad clinical spectrum which makes clinical diagnosis difficult, screening of patients with velopharyngeal dysfunction for a deletion 22q11 is indicated.

Conductive hearing loss and multiple pre- and supra-auricular skin defects: a variant example of the Branchio-Oculo-Facial Syndrome: We describe a 3-year-old girl with bilateral severe conductive hearing loss and multiple bilateral supra- and preauricular defects with unusual overlying thin skin. The severe conductive hearing loss is due to abnormal configuration of the ossicular chain. Multiple pre- and supra-auricular skin defects have been described in the Branchio-Oculo-Facial syndrome, and we propose that the findings in our present patient may be a variant manifestation of this syndrome.

We report on a 1-year-old boy with Mandibulo-acral dysplasia, a rare autosomal recessive syndrome (MIM 248370). He presented at the age of 6 months with short stature, scarce brittle hair and thin skin mainly on the skull with visible veins. The facial appearance was typical with micrognathia, prominent eyes and a thin nose. Hypoplastic terminal phalanges and acroosteolysis were present. Psychomotor development is normal.

A two-year-old boy with the combination of profound nerve deafness and semilobar holoprosencephaly associated with minor midline developmental anomalies is reported. In a review of the literature we could not find other examples of this possible syndromic association.

We report data on feeding and speech disorders in 50 patients with velocardiofacial syndrome. In order to contribute to delineation of type and etiology of feeding and speech problems, we compared the clinical findings in these patients with the reports in literature.

During the last 5 years, we diagnosed in Leuven 130 patients with a 22q11 deletion. The deletion was familial in 14 out of 110 index patients (12%), which is significantly less compared to previous studies. In 10 patients, the deletion was maternal, in 4 patients paternal. A cardiac defect was the main presenting symptom in 49% of patients. The other patients were ascertained through developmental delay (16%), behavioural disturbances (7%), otorhinolaryngological manifestations (6%), psychiatric manifestations (3%) and mental retardation (2%). In one patient hypocalcemia was the presenting symptom. In another patient the severe immune deficiency led to diagnosis. Most patients presented a wide variety of the classical features of the Velo-Cardio-Facial syndrome. Velopharyngeal incompetence, learning difficulties or mostly mild mental retardation were almost always present, whereas clinical significant hypocalcemia or immune disturbances were rare. Previously un(der)recognised features include polyhydramnios, renal malformations and laryngotracheamalacia or laryngeal stenosis.

The velo-cardio-facial syndrome (VCFS), due to a deletion in chromosome 22 on its long arm (22q11), is a leading cause of velopharyngeal dysfunction and cleft palate. With the recent finding of a deletion on chromosome 22q11 in these patients with velopharyngeal dysfunction, a routine test is available making the diagnosis of VCFS much more frequent than previously thought.

The additional hospital costs and the effects of cochlear implantation are described. From the start in 1994 until 1996 ten patients, 8 adults and 2 children, received a cochlear implant after careful preoperative selection. Only the 8 deaf adults implanted with the LAURA cochlear implant in the department of Otorhinolaryngology, Head and Neck Surgery of the University Hospital Leuven will be included in this retrospective analysis. In this study, the additional hospital costs associated with cochlear implantations are estimated. In estimating the costs, a differentation is made between 'fixed' costs and 'variable' costs. In general the costs of cochlear implantation is high: an average cost of 1,186,741, -Bef per implanted adult and a direct fixed cost of 262,880, -Bef for the computer requisites. To evaluate the effect of cochlear implantation a standard test, the AN-test battery, is used. In general, the cochlear implant enhances the speech perception scores in the postlingually deafened as well as in the prelingually deafened adults. After intensive training, all implanted adults of the University hospital Leuven could recognize the segmental aspects of speech with scores above the level of significance. The cochlear implant has also a positive psychological and social impact.

OBJECTIVE:To compare the efficacy and safety of long term use of ranitidine 150 mg bid, 300 mg bid and placebo in prevention of endoscopic and symptomatic relapse of reflux esophagitis in an international, double-blind, placebo controlled, parallel group study.PATIENTS AND METHODS:A total of 279 patients at least 18 years old from hospital out-patient departments with healed esophagitis (grade 0) with no or mild symptoms entered the study. Patients were randomly allocated to receive ranitidine 150 mg, 300 mg or placebo twice daily for 48 weeks. Patients returned for symptom assessments at eight-week intervals and for re-endoscopy every 16 weeks.RESULTS:Both ranitidine regimens were significantly more effective than placebo in preventing endoscopic and symptomatic relapse of reflux esophagitis (P=0.003 for ranitidine 150 mg bid; PCONCLUSIONS:Ranitidine 150 mg bid and 300 mg bid are safe and effective treatments in the prevention of reflux esophagitis relapse.

A retrospective analysis has been conducted of 57 labyrinthine fistulae found in 375 cholesteatoma cases, primarily treated by removal of the matrix of the cholesteatoma and covering the fistula with a mixture of bone paste and fibrin glue. CT-scan with slices of 1 mm demonstrated the fistula in almost 90% of the cases. Eighteen percent of the ears were pre-operatively totally deaf. Large fistulae are riskier than smaller ones for post-operative perceptive losses, but even in very large and multiple fistulae the hearing may be preserved in most cases.

BACKGROUND & AIMS: Intrasphincteric injection of botulinum toxin has been suggested as an alternative treatment modality in esophageal achalasia. A controlled trial comparing botulinum toxin, placebo, and pneumatic dilation is reported. METHODS: Sixteen patients received random intrasphincteric injections of either botulinum toxin or saline. The efficacy of treatment was assessed by symptom score, esophageal manometry, and scintigraphy. In case of failure, pneumatic dilation was performed. RESULTS: One month after injection, symptoms had improved in all patients treated with botulinum toxin (symptom score, 0.9 +/- 0.6 vs. 5.5 +/- 1.4; P < 0.02). In the placebo group, symptoms were unchanged in all patients, who were all dilated. Lower esophageal sphincter pressure decreased by 49% after treatment with botulinum toxin (P < 0.03) and by 72% after dilation (P < 0.01). Similarly, esophageal retention decreased by 47% after treatment with botulinum toxin (P < 0.02) and by 59% after dilation (P < 0.02). No significant difference in symptom score and esophageal function test results was found between patients treated with botulinum toxin injections and those undergoing dilation. However, 7 of the 8 patients in the botulinum toxin group required a second injection because of recurrent dysphagia. CONCLUSIONS: Treatment of achalasia with botulinum toxin was as effective as pneumatic dilation in relieving symptoms and improving esophageal function. The effect of the first injection was temporary, but the effect of the second injection lasted longer. (Gastroenterology 1996 Dec;111(6):1418-24)

Computed tomographic images, made about 6 months after the repair of fistulas of the lateral semicircular canal with a mixture of bone dust and physiologic adhesive, show the bony density of the reconstructed part of the canal.

The aim of the present study was to develop a dual-carbon-labeled breath test for simultaneously measuring gastric emptying rates of liquids and solids with significantly less radiation burden to the patient than the radioscintigraphic technique.A test meal was used in which the liquid phase was labeled with two markers, i.e., 3.7 MBq of 111In-DTPA and 100 mg of 13C-glycine; the solid phase also was dually labeled with 110 MBq of 99mTc-albumin colloid and 74 kBq of 14C-octanoic acid. Simultaneous radioscintigraphic and breath-test measurements were performed in 27 subjects, 10 normal controls and 17 patients with dyspeptic symptoms. Mathematic analysis of the excretion rate of labeled CO2 allowed the definition of four parameters, i.e., the gastric emptying coefficient, the gastric half-emptying time, the peak excretion time and the lag phase.There was a good to excellent correlation between the gastric emptying coefficient and the scintigraphic half-emptying time (r = 0.74 for liquids and r = 0.88 for solids), between the half-emptying time determined by breath test and the scintigraphic half-emptying time (r = 0.91 for liquids and r = 0.92 for solids), between the peak excretion time and the scintigraphic half-emptying time (r = 0.91 for liquids and r = 0.96 for solids) and between the lag phase of solid emptying determined by both techniques (r = 0.89).The dual carbon-labeled breath test is a valid, minimally invasive technique to measure the gastric emptying rate of both liquids and solids.

The gastrointestinal motor effects of the macrolide antibiotic, azithromycin, were compared with those of midecamycin acetate. The method of investigation consisted of intraluminal pressure measurements in the gastric antrum and upper small intestine by means of a low compliance perfused catheter system. Eleven healthy volunteers participated in the single blind, placebo-controlled study of both interdigestive and postprandial gastrointestinal motility. Azithromycin was administered by mouth in a single 500 mg dose or in two daily doses of 250 mg; midecamycin acetate was given in a dose of 600 mg b.i.d. The effect of midecamycin acetate on gastric antral and jejunal motility was not significantly different from that of placebo. This was true for both the interdigestive and the postprandial phases of gastrointestinal motility. Peroral treatment with azithromycin resulted in a statistically significant increase in the postprandial antral motility index as compared to placebo. This increase was observed in the distal antrum as well as in the proximal antrum. In addition, the gastric contractions were found to originate higher up in the stomach after azithromycin as compared to placebo or midecamycin acetate.

Both hepatic ischemia and chemotherapy are effective in the treatment of carcinoid liver metastases, but their effectiveness is often limited, partial and transient. It has been shown that, during intermittent occlusion of the hepatic artery with a surgically implanted occluder, no revascularisation from collaterals occurs. We studied the feasibility, the side-effects, the response to tumour measurements and hormonal excretions of a combined treatment of repeated hepatic ischemia and 5-Fluorouracil and Streptozotocin-administration in carcinoid liver metastases.

The results of startle and acoustic stapedius reflex measurements can be used to subclassify various types of fixation of the ossicular chain. Reflex measurements were performed on a group of subjects with normal hearing and on a group of patients with surgically verified ossicular chain fixation. In 97% of the subjects with normal hearing (n = 30), reproducible impedance changes were observed as part of a startle reaction and four different reaction patterns could be distinguished. In a subgroup of subjects with normal hearing who had a relatively, statistically significant, high acoustic reflex threshold, a characteristic response was found which was most probably caused by contraction of the tensor tympani muscle only. The same response was detected in 77% of the patients (n = 22) with otosclerosis. In the remaining 23%, no middle ear impedance changes occurred as part of a startle reaction. In five out of six patients with fixation of the malleus, no response was observed. Although the startle reflex measurement is a valuable tool for distinguishing between stapes fixation and multiple ossicular chain fixations, the results are not conclusive.

Due to the systemic nature of Whipple's disease the clinical presentation may be highly variable. The diagnosis may therefore be unduly delayed. If untreated, Whipple's disease is still potentially lethal. In contrast, the endoscopic findings as they are observed in the postbulbar small intestine and the light microscopic picture of small intestinal biopsies are almost pathognomonic. Out of a group of 18 patients (14 male, 4 female, mean age = 45 yrs), 12 patients were diagnosed using upper gastrointestinal endoscopy and duodenal biopsy, while six patients were diagnosed only by a small intestinal capsule biopsy. The clinical history prior to diagnosis lasted from 1 m to 22 yrs (mean = 3 yrs 6 m) in the first group and from 4 yrs to 21 yrs (mean = 12 yrs 6 m) in the second group. The endoscopic findings at the time of diagnosis were: oesophagitis (1/12), erosive gastritis (4/12), atrophic gastritis (2/12), severe erosive bulbitis (3/10), pathognomonic post-bulbar duodenal lesions (9/12). In 20% of the patients the endoscopic lesions had disappeared 6 m after antibiotics while the lesions had disappeared in all cases 9 m after therapy, despite the fact that PAS positive macrophages remained present in the endoscopic biopsies for years. All patients were treated with antibiotics (8 tetracycline alone, 4 tetracycline, streptomycin and penicillin, 6 trimethoprim). Five patients (27%-4 of the tetracycline group) relapsed within 2 to 20 yrs after the initial diagnosis. Three of these patients (3/5) had typical duodenal lesions on endoscopy at that time.

The gastrointestinal motor effects of the macrolide antibiotic, clarithromycin, were compared with those of midecamycin acetate. The method of investigation consisted of intraluminal pressure measurements in the gastric antrum and upper small intestine by means of a low compliance perfused catheter system. Six healthy volunteers participated in the single-blind, placebo-controlled study of both interdigestive and postprandial gastrointestinal motility. Clarithromycin was administered by mouth in a dose of 250 mg b.i.d.; midecamycin acetate was given in a dose of 600 mg b.i.d. The effect of midecamycin acetate on gastric antral and jejunal motility was not significantly different from that of placebo. This was true for both the interdigestive and the postprandial phases of gastrointestinal motility. Oral treatment with clarithromycin (250 mg, b.i.d.) resulted in a statistically significant increase in the postprandial number of antral contractions per hour as well as in the postprandial antral motility index, as compared to placebo.

The effect was studied on gastrointestinal motor activity of three different macrolides (erythromycin, roxithromycin and midecamycin acetate), administered by mouth in therapeutic doses. This placebo-controlled study was performed in 12 normal human subjects by means of intraluminal pressure measurements in the gastric antrum, duodenum and upper jejunum. In each subject, three manometries were done for 5 h in the interdigestive period and for 3 h postprandially. In the interdigestive period, midecamycin acetate did not affect the characteristics of the gastric migrating motor complex (MMC) and did not increase the number of antral contractions or the gastric motility index as compared to the placebo. Erythromycin and roxithromycin increased the number of antral contractions (24.5 +/- 11 versus 15.2 +/- 7 and 28.4 +/- 12 versus 14.9 +/- 5.9 respectively) and the motility index (4.05 +/- 0.5 versus 3.17 +/- 0.6 and 4.38 +/- 0.2. versus 3.64 +/- 0.7 respectively) as compared to the placebo. In the postprandial period, the number of antral contractions was not significantly increased by any of the three antibiotics. The postprandial antral motility index was not significantly increased by midecamycin acetate. In contrast, the postprandial antral motility indexes after erythromycin (4.4 +/- 0.5) and after roxithromycin (4.3 +/- 0.2) were significantly greater than after the placebo. In the upper small intestine, erythromycin elicited an increased number of phase-III-like activity events and roxithromycin shortened the MMC cycle length. Midecamycin acetate had no effect on interdigestive upper jejunal motility. The postprandial jejunal motor activity was not altered by any of the three antibiotics neither during the interdigestive nor the postprandial periods.(ABSTRACT TRUNCATED AT 250 WORDS)

Esophagitis is a very common disorder. The etiology cna be highly variable and is not always clear from the biopsy. The main microscopic inflammatory lesions are located in the epithelium. They consist of an increase in inflammatory cells, either polymorphs or mononuclear cells, or both. They are associated with architectural mucosal changes. It is often difficult or impossible to distinguish reflux esophagitis from drug-induced or viral esophagitis. Yet some microscopic patterns are characteristic and provide information on the etiology of the lesions.

Vagotomy coincides not only with a reduction of the cephalic phase of secretion but also with a significant reduction of the motor activity of the stomach. Electrical and mechanical activity of the gastric wall after truncal vagotomy were verified in animal experiments (dog n = 5) by means of implanted electrodes and pressure transducers. Longlasting motility disturbances expressed as a disorganisation of the basic electrical rhythm occurred in the gastric wall. According to the pattern periods of tachygastria and tachyarrhythmia were identified. Those periods interrupted the regular fasted motility and persisted in the postprandial period. Simultaneous registration of the mechanical activity of the gastric wall during disorders of the electrical rhythm revealed a complete absence of contractility which probably is the pathophysiological correlate for the frequently described delayed gastric emptying after vagotomy.

Laser has become in the recent years an important therapeutic tool for treating esophageal cancer in a palliative setting aiming to reopen the tumor stenosis. The literature shows that the initial enthusiasm for laser, compared with other methods--especially endoprosthesis--has somewhat been tempered because the success rate in restoring a normal food intake was lower than expected (65-68%). Although the complication rate is low, repeated therapy sessions are needed to maintain the lumen open. This constitutes a major drawback in terms of patient acceptability. Variations in the therapeutical methods (contact laser, photodynamic therapy, ...) have not added up to now significant value to laser therapy. Specific indications for laser therapy versus endoprosthesis are discussed and should bring both therapeutic modalities to a more considered application.

A review of the literature is done about the epidemiology and aetiology of esophageal cancer. Esophageal cancer is a relatively uncommon neoplasm in Western countries with a very poor prognosis. In industrialized countries alcohol and tobacco are the major risk factors. Nutritional factors play also an important role in the aetiology of esophageal cancer, particularly a diet rich in cereal but poor in fresh fruit and vegetables, accounts for some of the geographic differences. Several predisposing disorders for esophageal cancer are known and include Barrett's esophagus, achalasia, chronic strictures due to corrosive substances, tylosis, coeliac disease, and the Plummer-Vinson syndrome. The clinical manifestations are also discussed.

The authors review the pathological classification of chronic pseudo-obstruction syndromes, the differential diagnosis of these syndromes in order to rule out an obstructive lesion, the differential diagnosis of idiopathic chronic pseudo-obstruction syndrome and systemic sclerosis, the diagnostic contribution of oesophageal manometry and of gastro-intestinal manometry and electromyography, and finally the treatment of these syndromes. The authors mention also their experience in the treatment of severe diabetic gastroparesis with erythromycin, agonist of the gastric and duodenal motilin receptors. In 10 patients compared to controls, delayed gastric emptying for solid and liquid foods was normalized after intravenous injection of 200 mg erythromycin versus placebo.

Primary esophageal motility disorders consist of a complex group of motor disturbances, affecting the characteristics of esophageal contractions, occurrence of peristalsis and lower esophageal sphincter function. The medical treatment is still challenging because of the absence, except for Achalasia, of generally agreed criteria for diagnosis and the still unresolved relationship between esophageal symptoms and some motor abnormalities. In Achalasia, the medical therapy does not constitute a main role and should be reserved to selected conditions. Current medical therapies for Diffuse Esophageal Spasm and Esophageal Chest Pain are often considered less than satisfactory, however, a better physiopathological knowledge of these conditions might produce a more appropriate therapeutic management of the patients with continual and disabling symptoms.

In a series of 100 surgically treated patients, Zenker's diverticulum (ZD) appeared mostly as a typical geriatric disorder (50% over 70 years) in which not only oesophageal symptoms but also pulmonary symptoms (37%) may lead to a life-threatening situation. In 60% of the patients, associated upper gastrointestinal pathology was observed, most frequently being gastro-oesophageal reflux (30 patients). In 30% of the manometric studies of the oesophageal body and lower oesophageal sphincter, clear pathological patterns were observed. Morphological examinations, enzymohistochemistry, immunohistochemistry showed clear pathological changes not only at the level of the cricopharyngeal muscle but also at the level of the striated muscles of the cervical oesophagus. These clinical, manometric and morphological changes suggest that ZD is one expression of a more complex neurogenic disorder. They also justify the extramucosal myotomy of the cricopharyngeal wall and the striated muscle wall of the cervical oesophagus as well, as the cardinal step of operation. This myotomy was combined with a diverticulopexy resulting in no post-operative mortality and a minimum of morbidity. The mean longterm follow-up in this series is 4 years, showing excellent and very good results in 96% of the patients for the oesophageal symptoms and in 92% for the full spectrum of oesophageal and pulmonary symptomatology. With this single step operation, no recurrence has been seen seen as opposed to the endoscopic procedure.